title: Genetic factors of susceptibility and of severity in primary biliary cirrhosis.
abstract: OBJECTIVE
  In primary biliary cirrhosis (PBC), pathogenesis is influenced by genetic factors that remain poorly elucidated up to now. We investigated the impact of sequence diversity in candidate genes involved in immunity (CTLA-4 and TNFalpha), in bile formation (10 hepatobiliary transporter genes) and in the adaptative response to cholestasis (three nuclear receptor genes) on the susceptibility and severity of PBC.
  
  
  METHODS
  A total of 42 Ht SNPs were identified and compared in 258 PBC patients and two independent groups of 286 and 269 healthy controls. All participants were white continental individuals with French ancestry.
  
  
  RESULTS
  Ht SNPs of CTLA-4 and TNFalpha genes were significantly associated with susceptibility to PBC. The progression rate of liver disease under ursodeoxycholic acid (UDCA) therapy was significantly linked to SNPs of TNFalpha and SLC4A2/anion exchanger 2 (AE2) genes. A multivariate Cox regression analysis including clinical and biochemical parameters showed that SLC4A2/AE2 variant was an independent prognostic factor.
  
  
  CONCLUSIONS
  These data point to a primary role of genes encoding regulators of the immune system in the susceptibility to PBC. They also demonstrate that allelic variations in TNFalpha and SLC4A2/AE2 have a significant impact on the evolutive profile of PBC under UDCA therapy.
authors.affiliation: UPMC University of Paris 06, UMRS_893, CdR Saint-Antoine, F-75012 Paris, France. raoul.poupon@sat.aphp.paris.fr
authors.forename: Raoul
authors.initials: R
authors.lastname: Poupon
authors.forename: Chen
authors.initials: C
authors.lastname: Ping
authors.forename: Yves
authors.initials: Y
authors.lastname: Chrétien
authors.forename: Christophe
authors.initials: C
authors.lastname: Corpechot
authors.forename: Olivier
authors.initials: O
authors.lastname: Chazouillères
authors.forename: Tabassome
authors.initials: T
authors.lastname: Simon
authors.forename: Simon C
authors.initials: SC
authors.lastname: Heath
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
authors.forename: Renée E
authors.initials: RE
authors.lastname: Poupon
authors.forename: Chantal
authors.initials: C
authors.lastname: Housset
authors.forename: Véronique
authors.initials: V
authors.lastname: Barbu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D000368:Aged; D027321:Anion Transport Proteins / Q000235:genetics; D015703:Antigens, CD / Q000235:genetics; D017920:Antiporters / Q000235:genetics; D060908:CTLA-4 Antigen; D016022:Case-Control Studies; D027963:Chloride-Bicarbonate Antiporters; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005602:France; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D053208:Kaplan-Meier Estimate; D008105:Liver Cirrhosis, Biliary / Q000235:genetics* / Q000276:immunology*; D000071518:Liver X Receptors; D008297:Male; D008875:Middle Aged; D057093:Orphan Nuclear Receptors; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D064606:SLC4A Proteins; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D027321:Anion Transport Proteins; D015703:Antigens, CD; D017920:Antiporters; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D027963:Chloride-Bicarbonate Antiporters; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D064606:SLC4A Proteins; C579496:SLC4A2 protein, human; D014409:Tumor Necrosis Factor-alpha